Responsabilidades Eticas Acta Tropica2009

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Responsabilidades Eticas Acta Tropica2009

  1. 1. Acta Tropica 112S (2009) S53–S62 Contents lists available at ScienceDirect Acta Tropica journal homepage: www.elsevier.com/locate/actatropica An ethics perspective on responsibilities of investigators, sponsors and research participants Roma Chilengi ∗ University of Oxford and Kemri-Wellcome Trust Research Programme, Kilifi, Kenya a r t i c l e i n f o a b s t r a c t Article history: The major international guidelines for health research have come a long way in setting standards and Available online 8 August 2009 providing direction on acceptable practices for the conduct of research. However, the responsibili- ties of the key players have generally been addressed in a rather uncoordinated manner, and there Keywords: still remain gaps in addressing the responsibilities of some of the key players in the research set- Responsibilities ting. Investigators and sponsors This paper is a review of crosscutting guidelines and mix of the key responsibilities of investigators, Research participants and communities sponsors, study participants together with their communities. Some new responsibilities for the partic- Regulatory authorities Ethics committees ipants and research institutions have be suggested based on understanding and practical experience as they are not described in any traditional literature. © 2009 Elsevier B.V. All rights reserved. 1. Introduction tory authorities who have “unquestionable final” authority need also to have a set of good responsibilities to uphold. The research When medical research is conducted, many systematic activi- participants as well, who in most cases are “vulnerable subjects of ties take place involving multiple players. The scientific questions research” who must indeed be protected, should also have some and rationale for the study are developed; funding is sourced, pro- amount of responsibilities—especially that they should in one way tocols are written, approvals are sought, teams and trainings are or another draw benefits in the process. This review has been based established, research communities are engaged, study participants on the following international guidelines: the Belmont Report, consent to be researched on, data and samples are collected, anal- CIOMS guidelines, EU Directive, Helsinki Declaration, US-FDA reg- yses take place and finally reports or manuscripts are published. ulations, ICH-GCP, Nuffield Council on Bioethics, South African Historically, each of these aspects has generated a lot of attention Medical Research Council guidelines, WHO guidelines on Ethics, ranging from heroic acts of excellence to misconduct and tragedies. UNAIDS for biomedical HIV prevention trials, National Health & Over time, many guidelines have emerged to help regulate and set Medical Research Council of New Zealand, and other literature. standards for the conduct of various research activities and in the These guidelines have generally been observed to take a nega- process, sets of internationally accepted responsibilities of various tive view of medical research concentrating on the need to avoid players have been described. In this paper, such commonly quoted harm rather than the need to provide benefits for patients (Nuffield guidelines have been reviewed, identifying and knitting together Council on Bioethics, 1999). key responsibilities for the major players involved in research. Therefore, the aim of this paper is to address from an ethical Where such responsibilities have not been defined, suggestions of perspective, the moral obligations that the various stakeholders in the same have been made with a view to trigger efforts to address biomedical research inevitably inherit by virtue of being in their responsibilities of those players, and of note are the regulatory state either as research participants themselves, researchers and authorities and study participants. their institutions, sponsors of the research, data safety monitor- It is clear and perhaps rightly so, that current guidelines have ing boards, community advisory boards, regulatory authorities or focussed on carefully describing responsibilities of investigators committees that review and approve the research. and sponsor. However, it is the author’s opinion that the regula- The general basis being four fundamental ethical principles—fundamental in the sense that they are irrefutable human rights which transcend time, geography, race, culture, ∗ Tel.: +254 41 7522155; fax: +254 41 7522390. socio-economic class, age and other boundaries that separate E-mail address: Rchilengi@kilifi.kemri-wellcome.org. human beings. See Text Box 1 . 0001-706X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.actatropica.2009.08.004
  2. 2. S54 R. Chilengi / Acta Tropica 112S (2009) S53–S62 the research derives from having sought accepted medical care or Box 1: Fundamental ethical principles and their appli- having been selected from the general public because of known or cations in biomedical research. suspected abnormality (45CFR part 46, 2005, South African Medical Principle Description Application Research Council, 1993). Autonomy Human beings are born as Informed consent. autonomous agents. This 2.2. When does research include human participation? autonomy gives them rights to self-determination that must be respected. Autonomy demands The term research may be very general. Some studies which that the wishes of all persons still qualifying as research, may not actually involve living human must be respected and we do beings, but may be on samples or information obtained from so by asking their opinion or humans. For example, research that involves tissue specimens, willingness to get involved or not. medical records, genetic material, behavioural and/or biomedical Non-maleficence “Primun non nocere” Latin Evaluate foreseeable assessments, and treatments. Consequently, ethical and/or legal translation for first, do no risks and minimize obligations to protect human participants also apply to research harm. Research must primarily harm. that uses: and actively seek not to do harm regardless of the extent • Bodily materials, such as cells, blood or urine, tissues, organs, and of potential good that may arise from the research. hair or nail clippings, even if the researcher did not collect these Beneficence While minimizing harm, Maximize benefits materials. research must be of benefit to • Residual diagnostic specimens, including specimens obtained for individuals and society at large. routine patient care that would have been discarded if not used Beneficence is a group of norms for providing benefits, for research. and balancing benefits against • Private medical information, such as medical data that can be risks and costs. readily identified with individuals, even if the information was Justice A group of norms for Fair subject selection not specifically collected for the study in question. Research on distributing benefits, risks and and fair distribution of costs fairly. The benefits of benefits. cell lines or DNA samples that can be associated with individuals research must equitably be falls into this category. shared by those who bore the cost and risk of the research. Social, economic and/or behavioural information for health research purposes (Nuffield Council on Bioethics, 1999). 2.3. Why must participants take responsibility? It is important at this stage to emphasize that this paper has a bias to specific guidelines for the conduct of clinical trials involved The fundamental ethical principle of Justice requires “fairness” in development of medicinal products. or “entitlement”; it implies giving to each his/her due. Justice requires that “equals be treated equally and un-equals unequally” 2. Participants (45CFR part 46, 2005). This means that human beings as moral equals should be treated equally unless there must be a reasonable In this paper, the following terms “participant, volunteer, and justification for treating them differently. The principle of justice subject” have been used interchangeably to mean the individual. demands fairness in the treatment of individuals and communi- ties and the equitable distribution of the burdens and benefits of 2.1. Who is the research participant? research. The extrapolation of the application of this principle is that the “fruits of research must principally benefit those that bore The human participant is a living individual about whom (and the risks of the research”. In other words, humanity owes the enjoy- includes specimen taken from them), a researcher obtains either: ment of health care to research, and as such to enjoy the outcomes of research, individuals within our communities must bear the risk (1) Data through intervention or interaction with the individual; of that research. This has important implications for such issues or as choice of study population, recruitment into study, study and (2) Identifiable private information (45CFR part 46, 2005). post-study benefits, etc. Secondly, the fundamental principle of autonomy requires that In other words, this is the individual upon whom the investiga- the wishes and choices of an individual be respected (Belmont tor performs research. In the course of participating in a research Report, 1979). The word autonomy comes from two Greek words: study, a participant may provide information to investigators about nomos (“rule”) and autos (“self”), giving it the literal meaning of other persons, such as a spouse, relative, friend, or social acquain- “self-rule” or “self-governance”. Autonomy implies an individual tance. The information may be sensitive (e.g., regarding alcohol or who is master of himself/herself and can act, make free choices and drug use, diet, or lifestyle) and personal. These other persons are take decisions without the constraint of another. Informed consent referred to as “third parties.” Nevertheless, investigators should is a derived application of this principle such that an individual has treat all research information about individuals as confidential. the right to consent to take “risks” as long as they understand fully Identifying information, whether about a human participant or a the implications of their choice. The necessary pre-conditions of third party, should be kept secure and protected from inappropriate autonomy are thus, competence (the capacity to be a moral agent), disclosure. and liberty or freedom. Research may be done on participants who are either healthy Therefore, as autonomous beings, we inevitably assume respon- or unwell. In this context, a healthy participant is one who is not sibilities for whatever choices we make, and this includes known to suffer any illness relevant to the proposed study, and participation in research, provided the prevailing conditions enable is within the ordinary range of body measurements. On the other the individuals to exercise their right to self-determination. For hand, patient status refers to an individual whose participation in most studies to succeed, the research participant must comply to
  3. 3. R. Chilengi / Acta Tropica 112S (2009) S53–S62 S55 the requirements of the protocol, otherwise the set answers may and should be able withdraw participation should they find that not be fully answered. their interests are no longer satisfied by continued participation. In resource constrained settings like Africa, this can be practically 2.4. What are the responsibilities of the participants? challenging as most participants are likely to continue in research for want of options to obtain even the most basic of health care There are numerous implied responsibilities of a participant in (Pool and Wenzel, 2005). research. In this paper, they are summed into three main categories. The above issues notwithstanding, addressing responsibility when it comes to research involving minors (dependent children 2.4.1. Responsibility to understand that this is research below legal age of responsibility) remains an ethical dilemma. Participants must have a fair understanding of what research is. Although by default, parents and guardians are made to assume In the context of clinical trials, it is akin to “experimentation”, and this responsibility, it is remains debatable whether this is the most thus their choice to participate, after being given adequate infor- appropriate paradigm in view of the points raised above which, mation and explanations, implies that they volunteer to be objects arguably, a minor cannot be accountable for. According to CIOMS of that experiment. Participants must be aware that it is not an guideline 9; “When there is ethical and scientific justification to con- obligation to participate in the research and neither must it be a duct research with individuals incapable of giving informed consent, pre-requisite to accessing routine medical nor other social services the risk from research interventions that do not hold out the prospect publicly available. of direct benefit for the individual subject should be no more likely and If they understand and accept that the research is intended for not greater than the risk attached to routine medical or psychologi- their own good and ultimately that of their community and society cal examination of such persons. Slight or minor increases above such at large, they should thus, commit themselves to the success of that risk may be permitted when there is an overriding scientific or medical research in as far as what is expected of the participants. In essence rationale for such increases and when an ethical review committee has the success of the research is highly dependent on the cooperation approved them”. of the participant in being available to meet the protocol activi- Guideline 10 further addresses the specifics of involving chil- ties, provide information or specimens. It is however important at dren in research, to which an emphasis may be added: “There must this point to note that there are key requirements for the informed be direct benefit to the individual minor, and measures to minimize consent process to be considered ethically sound, i.e. (1) there has the foreseeable risks must be categorically clear” (CIOMS, 2002). to be adequate information shared; (2) the potential subject must have competence; (3) there must be comprehension and (4) the atmosphere must be free from coercive elements (45CFR part 46, 2.5. Community representatives 2005; World Medical Association, 2008). In contemporary times, these responsibilities have been rightly weighed on the investiga- Communities constitute important stakeholders who must tor; but it is however obvious that here remains a sufficient share equitably participate in research. However, special attention must of responsibility that the participant has to bare. be paid to particular categories of communities to avoid ill-formed In situations where the participant is a minor or somehow perceptions based on cultural, social, spiritual or economic misun- incompetent of giving informed consent, the parent or legally derstandings. “To misrecognise or fail to recognise cultural difference acceptable guardian assumes this responsibility (World Medical can inflict harm, can be a form of oppression, imprisoning someone Association, 2008; ICH-GCP E, 1997). (or a group) in a false distorted model of being- Research cannot be difference-blind” (NHMRC, 2003). Case examples here include spe- 2.4.2. Responsibility for risk-benefit analysis cial considerations for research involving the poorest communities As autonomous beings, participants must be able to make judge- in sub-Saharan Africa, or Aboriginal Maori people of New Zealand, ment of what risks they may be committing themselves to by san people of Kalahari desert or any other groups of human beings accepting to participate in research. This is why “competence” is a who for historical or evolutionary reasons may be distinctly dif- critical requirement, because the participants must be able to eval- ferent. Useful guidelines are available for advising engagement to uation whether the risks they are taking are consistent with their such communities (NHMRC, 2003; HRC, 2008; Lavery et al., 2007; own interest. The participant should be able to make judgement UNAIDS, 2007). that their perceived benefits of participation reasonably outweigh To ensure the ethical and scientific quality and outcome of the clearly present and foreseeable risks of the research. In other proposed research, its relevance to the affected community, and words, after having been given the necessary information by the its acceptance by the affected community, researchers and trial researchers and time to ask questions, the prospective participants sponsors should consult communities through a transparent and should weigh the risks and benefits of participation before making meaningful participatory process which involves them in an early a decision. and sustained manner in the design, development, implementa- It is important to recognize the fact that in most under developed tion, monitoring and distribution of results (Molyneux et al., 2007). communities, and especially for therapeutic research, the distinc- Community engagement may be arranged through local com- tion between medical service and research is hard to make and munity leaders such as chiefs, community health workers, or participants may not always be in a position to realize the impli- local civil authorities. Community Advisory Boards (CABs) are cations of their choices. However, this is why structures exist to increasingly being established as a mechanism for community re-enforce the protections by way of protocol approval process by engagement in research. ethics committees and regulatory authorities. In general community representatives help to achieve commu- nity engagement aimed at, but not limited to the following: 2.4.3. Responsibility to maintain right to autonomy The research participant is primarily responsible for his or her own safety and wellbeing. They must be able exercise their right • Ensuring that communities buy into the relevance of research; to withdraw their voluntary participation in the research when • Enhancing cultural and practical acceptability; they perceive that their interested may be in jeopardy at any stage • Community ownership, responsibility and authority; during the research. They are therefore responsible for contin- • Minimizing community disruptions on major activities and cul- uous evaluation of their commitment to participate in the trial tural norms;
  4. 4. S56 R. Chilengi / Acta Tropica 112S (2009) S53–S62 • Avoid exploitation bearing the perspectives of the lay commu- Medical Association, 2008; 45CFR part 46, 2005; CIOMS, 2002). The nity; researcher’s principle obligation is to promote the safety and well • Avoid unfair distribution of benefits of research; and being of the participants and this entails that research involving • Take into account social, cultural and political hazards human participants is only justifiable if the benefits of participation outweighs the foreseeable risks. The spirit of this paper is to stimulate debate and discussions Less emphasized and worth pointing out is the Helsinki point 17 that will lead to development of guidelines and sets of responsi- specifically singles out research in vulnerable populations which bilities for such community organs. Surely, in order to hold such must be responsive to the health needs of that population and key positioning in research, it must come with some clarity on . . . “reasonable likelihood that the community stands to benefit from responsibilities as well. the results of the research” (World Medical Association, 2008). This implies that the investigators must make a reasonable evaluation 3. Researchers [investigators] to ensure that there is some foreseeable benefits primarily to the participants and, or their communities. Implicit in this guidance is A researcher is the individual who undertakes the study. This an obligation to the investigator to negotiate and ensure that the term may be used synonymously with “investigator”, who accord- research being proposed somewhat meets this requirement. Fur- ing to GCP is: the person who takes responsibility for the conduct ther, CIOMS 10 requires the sponsor and the investigator to make of the trial or study and the study site (ICH-GCP, 1997). This paper every effort to ensure that (i) the research is responsive to the health has not taken the regular approach of listing the responsibilities, needs and the priorities of the population or community in which it but has focussed on the fundamentals and proposes categorisation is to be carried out, and (ii) any intervention or product developed, of these responsibilities as owed to the various stakeholders. or knowledge generated, will be made reasonably available for the benefit of that population or community” (CIOMS, 2002). One 3.1. Intrinsic responsibility to self apparent mechanism to ensure that these complex responsibilities are met is by following recommendations on community consulta- An investigator ought to be conscientious. An investigator ought tion and engagement (Nuffieldbioethics, 2005; CIOMS, 2002; World to be qualified by training and experience in the specific field of Medical Association, 2000). research (ICH-GCP, 1997). This is applicable to any type of research that an investigator may want to undertake. For instance, if one 3.3. Responsibility to local authorities wants to conduct behavioural research, they must have qualifica- tions in the relevant social sciences field. In the case of physicians Investigators are hired and paid to conduct research following wanting to conduct medical research, the Declaration of Helsinki the legally approved norms and regulations in a country. The ICH- stipulates that “it is the duty of the physician in medical research GCP guidelines specifically raise responsibilities of the researcher to protect the life, health, privacy, and dignity of the human subject. to the local regulations and the authorities including: The physician’s knowledge and conscience are dedicated to the ful- filment of this duty” (World Medical Association, 2008). ICH-GCP • To understand and conduct their work according to the applicable adds that “the investigator should be qualified by education, train- regulatory guidelines; ing, and experience to assume responsibility for the proper conduct of • To observe any law(s) and regulation(s) addressing the conduct the trial, should meet all the qualifications specified by the applicable of clinical trials of investigational products; regulatory requirements” (ICH-GCP, 1997). The physician may com- • To adhere to all study related requirements, Good Clinical Practice bine medical research with medical care, only to the extent that requirements, and full compliance to approve protocols; the research is justified by its potential prophylactic, diagnostic or • Ensure that the Ethical Committee has approve the research therapeutic value. When medical research is combined with med- before it is implemented ical care, additional standards apply to protect the patients who • Provide direct access to records and permission to examine, are research participants. The investigator should be thoroughly analyse, verify, and reproduce any records and reports that familiar with the appropriate use of the investigational product(s), are important to evaluation of a clinical trial. Any party (e.g., as described in the protocol, in the Investigator’s Brochure, in the domestic and foreign regulatory authorities, sponsor’s moni- product information and in other information sources provided by tors and auditors) with direct access should take all reasonable the sponsor (ICH-GCP, 1997). precautions within the constraints of the applicable regulatory It is a particularly important responsibility for the investigator to requirement(s) to maintain the confidentiality of subjects’ iden- introspect on whether they have sufficient time to properly conduct tities and sponsor’s proprietary information. and complete a study and ensure that s/he has adequate resources to meet the requirements of the study. The CIOMS guideline 8 (2008) stipulates that “the investigator must ensure that potential 3.4. Responsibility to the global scientific community benefits and risks are reasonably balanced and risks are minimized”. Guideline 9 emphasizes extra caution when dealing with vulnera- The main objective and definition of scientific research is to col- ble people. lect, analyse and interpret data that should contribute to a body Lastly on this point, the publication of research findings must of generalizable information (45CFR part 46). It is important that observe ethical norms. Helsinki Declaration, principle 30 states: “In research findings be published, whether positive or negative so that Publication of the results of research, the investigators are obliged to the global scientific community can have access to the data. Further, preserve the accuracy of the results; negative as well as positive results individual researchers owe it to the global community to conduct should be published or otherwise be made publicly available”, (World their work in an ethically acceptable manner for the following rea- Medical Association, 2008). sons: 3.2. Responsibility to the participants and community • Generation of knowledge is critical to answering the health needs of the global community. Therefore, researchers are morally There are duties that are explicitly stated, and others are implied obliged to contribute to the alleviation of disease and other vices within international research guidelines (ICH-GCP, 1997; World affecting the human population in general.
  5. 5. R. Chilengi / Acta Tropica 112S (2009) S53–S62 S57 • Resources available for research globally are limited. Therefore, Laboratories should be sufficient for observing key good labora- individuals accessing these resources have a moral obligation to tory practice requirements. Equipments need regular maintenance ensure that the resources are used in the best way possible; and documentation of their performance. Laboratory certification • Biomedical research needs to continuously be justified through through external proficiency testing schemes and accreditation is the benefits that come out of it. Negative results should particu- desirable for excellence in research. Further, it is desirable that larly be also publicized to help other research groups who may institutions set up quality systems including internal monitors who be pondering on the same or similar research questions. This will regularly ensure that the institutional quality assurance pro- helps avoid further experimentation on human subjects when gramme is functional. scientifically important questions have already been answered. Transportation for staff and participants should be operated observing institutional policies. Vehicles and ambulances should 4. Research institutions be maintained in good functional state and this is best handled at institutional level and should not be dependent on individual Research institutions have particularly escaped the responsibil- projects. This is because some poorly funded projects run the risk ity lists described in most guidelines. Research takes place, and of compromising the institution’s reputation. should only be allowed through bonafide institutions that are nationally recognized and mandated to undertake research within 4.3. Ethical review their localities. In the case of non-governmental organizations, very clear mandates should be in place that holds such institutions Institutions must ensure that all research undertaken under accountable to the public system in order to ensure protection of their umbrella is appropriately reviewed and approved. It is the the interests of the wider public, and most importantly vulnerable responsibility of any institution allowing research to take place, participants. to also ensure that appropriate ethical review mechanisms are in Thus there should be institutional regulations or guidelines as place; either as institutional review boards, independent review well as checks and balances to protect the reputation of the insti- committee or national ethics review committees. tution. Where the committee is institutional, the institution must ensure that sufficient infrastructure exists and that the core oper- 4.1. Staff related responsibilities ations are supported to facilitate efficient procedure. Other details pertaining to operations and responsibilities of ethics committees Institutions must conform to local laws pertaining to hiring staff, are addressed later in this paper. conditions of service, and other fringe benefits applicable to its staff. In the context of developing countries, it is highly desirable that 5. Sponsor institutions ensure a staff development plan that would allow pro- gressive career development. The institution should ensure that According to the ICH-GCP guidelines in sections 1.53 and 1.54 adequate staff are in place to ensure that the research studies the sponsor is defined as “an individual, company, institution, or are efficiently conducted while observing legal requirements on organization which takes responsibility for the initiation, man- working hours and staff leave needs. The ethical imperative here agement, and/or financing of a clinical trial”. (ICH-GCP, 1997). An is that the institution needs to ensure that staff hired to serve on investigator is an individual who both initiates and conducts, alone research studies are appropriately qualified for their roles; wher- or with others, a clinical trial, and under whose immediate direc- ever indicated, institutions must be able to check that staff belong to tion the investigational product is administered to, dispensed to, appropriate professional bodies that ensure that conduct is within or used by participants. The obligations of a sponsor–investigator the expected professional norms. The institutions must also ensure include both those of a sponsor and those of an investigator. The that local labour laws are understood and observed and appropriate European Directive, cognizant of the potential importance of such administrative support is rendered to investigational staff. non-commercial studies, makes provision for simplified good man- The sponsor is obliged to provide indemnity cover for trial ufacturing practices conditions to accommodate such studies while related eventualities (ICH-GCP, 1997). It remains the responsibil- upholding the quality standards (EU Directive, 2001). ity of the institution to ensure that appropriate insurance policy The ethical imperative that constitutes a fundamental obliga- cover is in place for professional indemnity on the institution and tion for sponsors is the protection of the safety and well being its researchers. of actual and potential research participants. The detailed spon- sor responsibilities are ably addressed in the guidelines, however 4.2. Infrastructure related responsibilities for the purposes of this paper key sponsor responsibilities into five categories: It is the duty of the institution to ensure that their infrastruc- ture is adequate to support the research being conducted within the 5.1. Responsibilities to the funding authorities/shareholders institution. The administrative structure should be able to provide up to date financial structure to internationally acceptable account- It is important to emphasize that companies that sponsor ing standards to support research. The Administrative structure research are primarily employed to earn revenue for their share- must be able to offer legal guidance to investigators especially for holders. Thus, in whatever they do, it is important for the survival of dealing with contracts and other inter-institution agreements. their companies to ensure that sound decisions are made and these When product research is involved, it is the duty of the insti- may not always be based on purely moral considerations. The crit- tution to ensure that sufficient systems are in place to observe ical issue is to ensure that when sponsors meet the expectations of both good clinical practices and good laboratory practices. This has their shareholders and internal company policies, the research par- implications of ensuring that institutional policies address quality ticipants must not be unduly exploited. In essence, we need to find control and quality assurance process. To undertake phase I studies, a good balance between the company’s profit making nature, and the institution must ensure that at a minimum, emergency facili- ethical considerations of their research and developmental activi- ties with resuscitators are in place. Further, appropriately qualified ties. physicians and nurses must be trained and regularly updated on However, there are now many not-for-profit sponsors of emergency medicine. research, especially that funded through the public sector, philan-
  6. 6. S58 R. Chilengi / Acta Tropica 112S (2009) S53–S62 thropies and charity organizations. When organizations sponsor mended that sponsors deal directly with the ethical review boards, research in this context, requirements of the funding organizations but they must do so through their investigators. They must ensure must be fulfilled. The common arrangement requires that the bene- that before the study can be allowed to start, adequate review and ficiary organization takes on all sponsor related responsibilities and approval has been done by the legally mandated bodies both locally ensure that the funding authority is clearly free from any potential and internationally. litigations that may arise from the research. 5.2. Responsibilities to participants and their communities 5.5. Data safety monitoring boards [DSMBs] The fundamental obligation of sponsors to the participants and The DSMB is a relatively new phenomenon in clinical trials. It communities is to ensure that the research is safe, and that the is described as “a body of selected experts that monitors regularly benefits of participating in such research outweigh the potential data from a clinical trial, review and assesses the performance of risks of doing so. CIOMS guideline 10 specifically insists that all its operations, and makes recommendations as appropriate to the proposed research must be both responsive to the health needs of sponsor” (ICH-GCP, 1997; Lang et al., 2008). Their focus is on safety the communities where it is to be done, and must also show that the data, and their interim data reviews are done in the context of the knowledge generated or product developed will be reasonably be most recent scientific literature. Other terminologies are used for made available to those communities (CIOMS, 2002). This is par- the same concept such as Safety Monitoring Committee (SMC), and ticularly important in the developing world where typically, the Independent Monitoring Committee (IDM). research participants are vulnerable in many ways. Careful consid- The DSMB may be established by the sponsor to assess at inter- eration is required to ensure that the benefits of the research do vals the progress of a clinical trial, the safety data, the critical not otherwise unduly influence the decision making process of the efficacy endpoints, and to recommend to the sponsor whether communities and participants to be involved in research. to continue, modify, or stop a trial (ICH-GCP 1.25). Guidance on Three of the four fundamental ethical principles (beneficence, operations and requirements of DSMBs are still emerging and a non-maleficence and justice) all require that research leads to ben- comprehensive account of Lang et al. recommends the following efits for those who participate while potential risks be minimized situations to have DSMBs: as much as possible. This is a fundamental obligation; however, caution is advised when considering this matter which should be • Randomized control trials (RCT) evaluating clinical efficacy and handled on a case by case basis because of the complex impli- safety of an investigational new product; cations and variable socio-economic conditions. The local ethical • Controlled trials with mortality or severe morbidity as a primary review committee must play a key role in evaluating the proposed or secondary endpoint; benefits against the likelihood of coercion to participate in the • Early studies of a high risk new intervention; research. • Clinical trials where the design or data accrual is complex; • Where there is uncertainty about whether the data will lead to 5.3. Responsibilities to investigators and their institutions changes in the trial design; • Products or interventions being used as a new combination Sponsors also have specific obligations to the investigators and • Products that are unlicensed or used off label (outside marketed research institutions. The GCP has detailed responsibilities out- indication); lined, including selection of investigators, ensuring quality systems, • Trials involving vulnerable populations such as children, preg- provision of product and information, provide for patient care, nant women, and mentally impaired or very sick participants; insurance and sufficient monitoring of the research protocols for • Studies carried out in emergency situations; and compliance (ICH-GCP, 1997). • Studies where data may justify early terminations, especially for The sponsor must provide sufficient funding to undertake the safety reasons. research well. From an ethical perspective, enough budget must be allocated for patient care, medical and laboratory consumables, and ensure state of the art equipment for evaluation of safety parame- The terms of reference and details guiding the operations of ters. Further, the sponsor must ensure that there are sufficient care the DSMB should normally be articulated in a DSMB Charter. The facilities to deal with detection, reporting and treatment of medical Charter may be made available to ethics committees and regula- emergencies. tory authorities as may be required. Indeed some local authorities It is also critical for sponsors to ensure that no conflict of interest do require submission of the DSMB reports for their review. This exists when investigators are selected, and nearly all collaborative is especially so in complicated trials where the local authori- research currently includes signing official statements to attest a ties may not have the competence to review the progress of the lack of financial or other interests between the investigators and study. The DSMBs are generally empowered to review the ongo- the sponsor organizations. ing progress of the trial and may make recommendations to the sponsor for continuation, modification or even termination of the 5.4. Responsibilities to the local authorities study. A recurrent ethical debate around establishment of DSMB is A critical requirement is to ensure adequate reporting of safety around their independence and whether the DSMB statistician related matters to applicable Regulatory Authorities. As far as the should be totally independent or part of the study, and frequencies GCP guidelines are concerned, “applicable Regulatory Authorities” of interim analyses (Lang et al., 2008; Hrobjartsson et al., 2007). are given the utmost and final say on what must be observed. In Given the current convention, it is the responsibility of the spon- general, it is considered that the sponsor must seek to fulfil all sor, and the members of DSMBs (individually and collectively) to the regulatory requirements both internationally and locally. Early ensure that the DSMB is really independent in decision making and engagement and negotiation is recommended to allow for suffi- operate in the best interest of study participants’ safety. Regula- cient time to meet requirements before the study can begin. tory authorities, investigators as well as ethics committees are also The ethical review requirements are another part that the better placed to counter check and ensure that the DSMB meets its sponsor must be fully aware of and be able to satisfy. It is not recom- objectives.
  7. 7. R. Chilengi / Acta Tropica 112S (2009) S53–S62 S59 6. Regulatory authorities [RAs] The two WHO guidelines have addressed in depth, the descrip- tion of what ERB are, or are intended to be, recommended RAs are agencies that regulate medicines and are often referred compositions, what ethical review entails, how they should oper- to as Medicines Regulatory Authorities/Agencies (MRAs). These ate, reach decisions and communicate those decisions. Other may be national or supranational organizations established and publications have ably provided ethical framework for evaluating mandated to formulate and implement laws that regulate the whether proposed research is ethical (CIOMS, 2008; Emmanuel et business of medicines. RAs are established by local or regional al., 2000; Amdur and Elizabeth, 2002). In this paper a composite governments or authorities to be able to address the following view of looking at the responsibilities of ethics committees due to important medicines related matters: research participants, investigators, sponsors and local authorities are proposed. • Set and enforce standards or regulations for product quality, man- ufacturing (GMP) and marketing; • Review evidence (data) needed to approve a medicinal product; 7.1. Responsibilities to the participants • Review and regulate research and development of medicines Perhaps the greatest role of the ERB is to ensure that research especially in terms of GLP and GCP; • Labelling reviews and product promotion regulation; that is conducted among the communities that the committee rep- • Review and approve research studies aimed at developing spe- resents is ethical. This statement is loaded with all the details described in various guideline documents listing the various roles cific medicinal products; • Provide a mechanism for safety evaluation of approved medicinal and responsibilities. Critical to this obligation is to ensure that in its basic setup, composition, operations and follow up activities are products etc. such that the mandate of protecting research participants is car- ried out effectively. As research participants are often times, of low The key objective is to protect consumers/public against hazards socio-economic status and of low literacy rates, especially in Africa, associated with consumption of the medical products. RAs provide this responsibility is even heavier than it could be if the participants pre-market review of data assembled in support of applications for were less vulnerable. In many respects, this responsibility is similar market authorization to determine whether developers have tested to representing the “voiceless”. It could be argued in most research and established sufficient evidence for quality, safety and efficacy contexts that it is difficult for the target research participants to be for the intended use of the candidate product before granting mar- able to actually read, comprehend, analyse the risk posed by pro- ket authorization. They provide market controls and licensing of posed studies in order to make sound decisions on participation in medicines, import/export certification, inspections, surveillance, the research. and control of promotion. RAs are mandated to take legal actions In some worst case scenarios prevailing in some developing including suspension or revocation of authorizations and arraign- countries, the participants are so vulnerable that it is actually ment in courts of laws. “nearly impossible” for them to be able to even consider refus- In so far as medical research is concerned, RAs hold the supreme ing what researchers bring to them by way of research studies. In authority over the conduct of research under their jurisdiction. The such setups informed consent documents signed may not actually GCP guidelines subjugate the final decision making and specific mean the participants understand and accept the research. They positions to the RAs (ICH-GCP, 1997). All other guidelines approach may be willing to participate for many other reasons more impor- regulatory authority with similar absolute decision making posi- tant to them than the risks posed by the research. In the light of the tioning with the exception of the European Directive on clinical above therefore, this paper proposes that the ethics committees trials that seems to provide some instructions to the member state and its membership, individually and severally have the follow- authorities (EU Directive, 2001). ing moral obligations within the currently prevailing biomedical A case is made here for some set of regulations or guidelines research setup. for the RAs to be held by. Indeed other voices of decent have crit- icized both the ICH-GCP guideline as well as the authority of the US-FDA (Goodyear et al., 2009; Grimes et al., 2007). In the interest • The members must be qualified by training or role for which they of fairness and accountability, it might be good for the interna- are nominated to serve on the committee. Each member must tional community to come up some with sets of responsibilities that have a specific function for which they are nominated to serve would help set borders for RAs. It is particularly important for RAs and fulfilling that role must be the “moral” obligation owed to set in developing countries where, in the absence of full capacity to participants and the research community they represent. meet their obligation, the authorities are moving towards enforcing • Members must ensure that they review protocols to the best of all the powers attributed to them from the international guidelines. their abilities in order to protect the participants against the risks Much authority must be complementary with much responsibility that research may otherwise pose; and accountability; otherwise, there is a risk of that authority being • Corporately, the ERB must ensure that in its operations, safety misused or indeed abused. and well being of participants is of primary concern. This entails establishing procedures and mechanisms that require investiga- tors and sponsor to meet standards that satisfy and enhance the 7. Ethics committees protection of the well being of participants. • Oversight activities must be in place to ensure that the research There are many synonyms for committees that review biomed- that is approved is actually what is implemented. This oversight ical research protocols, but for the purposes of this paper, should include review of progress reports, safety issues arising terminologies are loosely used to mean the organ reviewing and from ongoing trials and actually physical follow up. approving biomedical research to safeguard the dignity, rights, safety, and well being of actual or potential research participants (WHO, 2000; Tedlock, 1983). Terms such as Independent Ethics If committees fulfil these kinds of responsibilities, healthy Committee (IEC), Institutional Review Boards (IRB), Institutional research environments would be promoted through which rele- Ethics Committee (IEC), National Ethics Committee (NEC), and vant research is promoted while unethical elements are detected Ethics Review Boards (ERB) are interchangeably used. and dealt with appropriately.
  8. 8. S60 R. Chilengi / Acta Tropica 112S (2009) S53–S62 Fig. 1. Interrelations among key players. The schematic representation of the interactions of the players. The arrows generally show the communication lines, flow of information or reports. 7.2. Responsibilities to investigators and their institutions research community interests are duly addressed through diverse representation on the ethical committee. By virtue of their role in the proposed studies, investigators The ERB must have clear procedure and requirements. This have a certain level of inevitable bias. It is the responsibility of the allows the sponsors of research to be able to take care of the condi- ERB to ensure that the research proposed is thoroughly reviewed, tions set by the ERB. Transparency is another important obligation not only to protect the participants, but also to improve the work especially owed to sponsors. It must be clear what issues the ERB of the investigators. The ethical approval should actually protect considers and reasons for non-approval of proposed studies must the investigator and the institution to the extent that unfore- be satisfactory. Conflicts of interest must clearly be addressed in seen problems can be publicly acceptable when they occur within a manner that decision making may not be influenced unduly by approved studies. The ethics committee is thus obligated to review whatever the conflicts may be. In short, ethics committees must all information that the investigators would use in communicating have documented clear requirements, standard operating proce- to potential participants including advertisements, informed con- dures, composition, schedule of meetings, and transparency in its sent forms, protocols, information collection tools etc. It would be routine operations. very helpful to investigators if ERBs served as an additional eye to Further, the ethics committee must provide assurance that the ensure that they do not allow scientific interests to blind them to research that they approach is actually what goes on in the field and potential ethical pitfalls. that they have mechanisms to detect defaulting investigators and The scientific aspects of research are also of key importance. have ability to enforce the required disciplinary actions in those sit- According to the Declaration of Helsinki, bad or poor science uations. In the absence of this capability, chances of both scientific is also unethical (World Medical Assembly, 2008). Thus, ethical and ethical misconduct remain very high. review systems must ensure that the science proposed is sound, by whatever mechanisms that may be available to the ERB. Some 7.4. Responsibilities to the local authorities institutions have separate scientific review before ethical review while others have combined scientific and ethical review (WHO, It has to be clear that ERBs also serve the public interest within 2000; Tedlock, 1983). the local contexts that they are established. Thus, it is of primary importance that the ERB draws its mandate from the local author- 7.3. Responsibilities to sponsors ities. It is desirable that a legal basis for the ERB establishment is enshrined within the local laws such as Acts of Parliament or other Part of the reason for the requirement that ERBs are multi- specific legal frameworks. disciplinary is to ensure that the key group interests are International laws such as the Universal Declaration of Human represented (WHO, 2000). In most situations, the sponsor cannot Rights of December 1948 specifically provide some protection to realistically be close enough to the community to really under- all human beings (United Nations, 1948). The General Assembly of stand local values and norms. In this regard, ERBs should show the United Nations adopted and proclaimed the Universal Declara- that the interests of the community they represent are well taken tion of Human Rights. One of the articles stipulates that ‘all human care of and this would provide assurance to the sponsors that beings are born free and equal in dignity and rights, and no one shall the chances of unethical conduct are minimal because the local be subjected to torture or to cruel, inhuman or degrading treatment
  9. 9. R. Chilengi / Acta Tropica 112S (2009) S53–S62 S61 or punishment’. These human rights are at an international level Beauchamp, L.T., Childress, F.J., 2001. Principles of Biomedical Ethics, Fifth Edition. which may be inaccessible to research participants some of whom Oxford University press. Belmont Report: Ethical Principles and Guidelines for Research involving Human may be poor and vulnerable. Thus ERBs operating within local legal Subjects. The National Commission for the Protection of Human Subjects of framework could be an immediate mechanism of protecting the Biomedical and Behavioural Research, April 8, 1979. interests of research participants. Code of Federal Regulations title 45- Public welfare Department of Health and Human Services, part 46 protection of human sub- The ERBs must also be answerable to a higher authority within jects. 2005; available on http://www.hhs.gov/ohrp/documents/ the local setup. An example from the US shows that the Department OHRPRegulations.pdf. for Health and Human subject Research oversees the operations of Chilengi, R., 2009. Clinical development of malaria vaccines: should earlier trials be done in malaria endemic countries? Hum. Vaccines 5 (9), 1–10. ERBs and has direct links to the FDA. This is a major gap in most Emmanuel, E., Wendler, D., Grady, C., 2000. What makes clinical research ethical? developing countries, where there is no firm oversight on opera- JAMA 283, 2701–2711. tions of ERBs (Nyika et al., 2008). International guidelines could also EU Directive, 2001/20/EC. Clinical trials directive by the European Parliament and the Council of the European Union. be more prescriptive on the specific responsibilities of ethics com- Hrobjartsson, A., Forfang, E., Haahr, M.T., Als-Nielsen, B., Brorson, S., 2007. Blinded mittees by which they should be held accountable to balance the trials taken to the test: an analysis of randomized clinical trials that report tests huge mandate allocated to them. for the success of blinding. Int. J. Epidemiol. 36, 664–665. Goodyear, M.F D.E., Trudo, L., Dominique, S., GodfreyF T., 2009. Does the FDA have the authority to trump the Declaration of Helsinki? BMJ 338, b1559. 8. Concluding remarks Grimes, D., Hubacher, D., Nanda, K., Schulz, N., Moher, D., Altman, D., 2007. The Good Clinical Practice guideline: a bronze standard for clinical research. Lancet 366 (9480), 172–174. Although experimentation on human subjects is undesirable ICH-GCP E6, 1997. International Conference on Harmonisation Guidance: Good (and clinical trials are a form of human experimentation), there Clinical Practices. Global Medical Education and Development. Available at is no other way to develop knowledge and disease alleviating tools http://www.icr-global.org. Health Research Council of New Zealand, 2008. Guidelines for Researchers on Health for medical practice. None of the animal models is sufficiently rep- Research Involving Maori. resentative of the human, and a number of interventions tested in CIOMS International Ethical Guidelines for Biomedical Research Involv- animals have repeatedly yielded disappointingly different results ing Human Subjects. Revised draft, January 2002; available on http://homepage.vghtpe.gov.tw/∼mre/goodexp/Fercap-Survey/CIOMS- in humans (Chilengi, 2009). Therefore, although animal models will 2002-Guidelines.pdf. always provide important information, research in humans is cur- Lang, T., Roma, C., Ramadhani, A.N., Bernhards, O., James, E.T., Wen, L.K., Geoffrey, rently inevitable; however, it must be directed by internationally A.T., 2008. Data safety and monitoring boards for African clinical trials. Trans. accepted guidelines. Royal Soc. Trop. Med. Hyg. 102, 1189–1194. Lavery, V.J., Grady, C., Wahl, R.E., Emmanuel, J.E., 2007. Ethical Issues in International As we apply the fundamental ethical principles it is important to Biomedical Research: A Case Book. Oxford University Press. strike reasonable balances. The dimensions of these moral princi- Molyneux, C.S., Peshu, N., Marsh, K., 2007. Trust and informed consent: insights from ples (in range and scope) needs to be carefully balanced (in weight community members on the Kenyan coast. Soc. Sci. Med. 61, 1463–1473. National Health & Medical Research Council of New Zealand, 2003. Values and and strength) (Beauchamp and Childress, 2001). The four principles Ethics: Guidelines for Ethical Conduct in Aboriginal and Torres Strait Islander being equally important, do not always carry the same weight and Health Research. scope at all times. For example, little children and other individuals Nuffield Council on Bioethics, 1999. The ethics of clinical research in devel- oping countries, available on http://www.nuffieldbioethics.org/fileLibrary/ with diminished capacity cannot have their right to autonomy at pdf/clinicaldiscuss1.pdf. the same scale as non-maleficence; likewise, beneficence cannot be Nuffield Council on Bioethics, 2005. The ethics of research related to health- applied with the same weight among vulnerable subjects as those care in developing countries: a follow up discussion paper, available on http://www.nuffieldbioethics.org/fileLibrary/pdf/HRRDC Follow- socio-economically well off. Thus, there is need to judiciously con- up Discussion Paper001.pdf. sider the implications of how we translate these ethical principles Nyika Aceme, Wenceslaus Kilama, Tangwa, G.B., Roma Chilengi, Paulina Tindana, lest we completely override justice while trying to uphold the oth- 2008. Capacity building of ethics review committees across Africa based on the ers (Lavery et al., 2007). Over enthusiastic enforcement of guideline results of a comprehensive survey. Developing World Bioethics, 1471–8731, doi:10.1111/j.1471-8847.2008. may ultimately be harmful to science and progress in research. Pool Robert, Wenzel Geissler, 2005. Medical Anthropology Text Book. In this manuscript, the most commonly cited international South African Medical Research Council, 1993. Guidelines on ethics for medical guidelines have been reviewed, assimilated and key players identi- research. Tedlock, D., 1983. Surveying and Evaluating Ethical Review Practices: The spoken fied together with their respective roles and duties. Rather than the word and the work of interpretation. University of Pennsylvania Press, Philadel- conventional listing of responsibilities, this paper has attempted phia. to interpret the responsibilities in the light of fundamental ethical UNAIDS, 2007. Good participatory practice guidelines for biomedical HIV prevention trials. UNAIDS/07.30E/JC1364E. principles and pulled them together into concise and targeted sets United Nations, 1948. Universal Declaration of Human Rights. Available at of core responsibilities to other stakeholders within the matrix of http://www.un.org/en/documents/udhr/. complex stakeholder inter relations in research settings (Fig. 1). World Health Organization, 2000. Operational guidelines for ethics com- mittees that review biomedical research, available on http://apps.who. Particular efforts have been made to identify the key players int/tdr/svc/publications/training-guideline-publications/operational-guide- whose responsibilities are less apparent and suggestions made as to lines-ethics-biomedical-research. what could be some of their key responsibilities. Notably, all guide- World Medical Association, 2008. Declaration of Helsinki. Ethical principles for research involving human subjects. Adopted by the 52nd WMA General Assem- lines correctly allude to research participants as the victims (or bly, Seoul, South Korea. potential victims) to be protected and must benefit from research; however, they fail to identify any responsibilities at all for these key players. Glossary 45 CFR: Code of Federal Regulations of the Unites States of America. Part 45 deals Acknowledgements with regulations governing protection of human subjects involved in biomedical research. I am grateful to Aceme Nyika and Vicki Marsh for critical review CIOMS: Council of the International Organization of Medical Sciences. The organi- and advice on this manuscript. zation provide guidance on research ethics with particular bias towards less developed countries. DSMB: Data Safety Monitoring Board. This is an independent board set up by the References sponsor of a trial to provide continuous review of safety matters and advise the sponsor on continuation of the study. Amdur, R, Elizabeth, B, 2002. Institutional Review Board: Management and Func- ERB: Ethics Review Board. This is a committee or board that reviews proposals of tions. Jones and Bartlett Publishers. biomedical research and provides approval when due safety and well being of
  10. 10. S62 R. Chilengi / Acta Tropica 112S (2009) S53–S62 potential participants is well addressed. Used here interchangeably with sev- GMP: Good Manufacturing Practice. International guidelines for the pharmaceutical eral similar acronyms including: IEC for Independent Ethics Committee, IRB for manufacture of medicinal products. Institutional Review Boards, IEC for Institutional Ethics Committee, and NEC for ICH: International Conference on Harmonization. The landmark conference that lead National Ethics Committee. to development and adoption of the GCP guidelines. EMEA: European Medicinal Agency. The international regulatory authority that over- RCT: Randomized Controlled Trial. A design of clinical research where study subjects sees development of medicinal products within Europe. are randomly allocated to one or the other arm of the study. EU Directive: European Union Directive. Law passed by the European parliament RA: Regulatory Authority. Government or regional bodies established to regulate the governing aspects of clinical research and product development. development and licensure of medicinal products. FDA: Food and Drugs Authority. The United States of America regulatory authority. UNAIDS: United Nations programme on HIV/AIDS GCP: Good Clinical Practice. International guidelines for the conduct of clinical trials. WHO: United Nation’s World Health organization. GLP: Good Laboratory Practice. International guidelines for laboratories that support environmental, animal and biomedical research.

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